CN111225918A - 具有三环部分的Toll样受体7(TLR7)激动剂、其缀合物及其方法和用途 - Google Patents
具有三环部分的Toll样受体7(TLR7)激动剂、其缀合物及其方法和用途 Download PDFInfo
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- CN111225918A CN111225918A CN201880065819.2A CN201880065819A CN111225918A CN 111225918 A CN111225918 A CN 111225918A CN 201880065819 A CN201880065819 A CN 201880065819A CN 111225918 A CN111225918 A CN 111225918A
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及具有式(I)、式(II)或式(III)结构的化合物,其中R1、R2、R3、R5、X1、X2和X3如本文中所定义,所述化合物为Toll样受体7(TLR7)的激动剂,且可用作用以刺激免疫系统的佐剂。一些此类化合物可以缀合物形式使用以靶向递送至预期作用的器官或组织。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119(e)主张2017年8月16提交的美国临时申请第62/546,151号的权益;该申请的公开内容以引用的方式并入本文中。
技术领域
本发明涉及Toll样受体7(“TLR7”)激动剂及其缀合物,以及此类激动剂及其缀合物的制备和使用方法。
背景技术
Toll样受体(“TLR”)为识别病原体相关分子模式(“PAMP”)的细胞表面受体。TLR通过结合相应PAMP而活化,其用信号发送病原体的可能感染且刺激免疫系统以对抗该感染。人类具有11种TLR,称为TLR1至TLR11。
通过激动剂活化TLR(主要研究TLR7)可通过刺激免疫反应而对疫苗和免疫疗法剂在治疗除真正病原体感染外的各种病状中的作用具有辅助作用。
TLR7识别与单股RNA病毒相关的PAMP。其活化诱导诸如IFNα和IFNβ的I型干扰素分泌(Lund等人2004)。TLR7具有两个结合位点,一个用于诸如ssRNA40的单股RNA配体(等人2007)且一个用于鸟苷(Zhang等人2016)。
TLR7可结合至类鸟苷合成激动剂且由其活化,此类激动剂诸如基于1H-咪唑并[4,5-c]喹啉骨架的咪喹莫特(imiquimod)、雷西莫特(resiquimod)和嘎德莫特(gardiquimod)。
还已知基于喋啶酮分子骨架的合成TLR7激动剂,实例如已处于2期临床试验的威沙立德(vesatolimod)(Desai等人2015)。据报导,威沙立德的效能比相应的嘌呤-8-酮化合物的效能小100倍,如通过IFN-α诱导所测量(Roethle等人2013)。
其他合成TLR7激动剂基于通常根据式(A)的类嘌呤骨架:
其中R、R'和R”为结构变量,其中R”通常含有未经取代或经取代的芳环或杂芳环。
具有类嘌呤的生物活性分子及其用于治疗诸如纤维化、炎性病症、癌症或致病性感染的病状的用途的公开案包括:Akinbobuyi等人2015b和2016;Barberis等人2012;Carson等人2014;Ding等人2016、2017a和2017b;Graupe等人2015;Hashimoto等人2009;Holldack等人2012;Isobe等人2009a和2012;Jin等人2017a和2017b;Peterson 2014;Pryde2010;和Seifert 2015。
基团R”可为吡啶基:Bonfanti等人2015a和2015b;Halcomb等人2015;Hirota等人2000;Isobe等人2000、2002、2004、2006、2009a、2011和2012;Kasibhatla等人2007;Koga-Yamakawa等人2013;Musmuca等人2009;Nakamura 2012;Ogita等人2007;和Yu等人2013。
Bonfanti等人2015b公开了TLR7调节剂,其中一个大环跨越嘌呤部分的两个环:
TLR7激动剂可与搭配物分子缀合,该搭配物分子可为例如磷脂、聚(乙二醇)(“PEG”)或另一TLR(通常为TLR2)。例示性公开案包括:Carson等人2013、2015和2016;Chan等人2009和2011;Lioux等人2016;Maj等人2015;Ban等人2017;Vernejoul等人2014;和Zurawski等人2012。还已公开了与抗体的缀合:Akinbobuyi等人2013和2015a,和Gadd等人2015。常见缀合位点位于式(A)的基团R”处。
还已公开基于5H-吡咯并[3,2-d]嘧啶骨架的TLR7激动剂。参见Cortez等人2017a和2017b;McGowan等人2017;和Li等人2018。
Jensen等人2015公开了阳离子脂质媒介物用于递送TLR7激动剂的用途。
一些TLR7激动剂(包括雷西莫特)为双重TLR7/TLR8激动剂。参见例如Beesu等人2017;Lioux等人2016;和Vernejoul等人2014。
还已公开基于5H-吡咯并[3,2-d]嘧啶骨架的TLR7激动剂。参见Cortez等人2017a和2017b;McGowan等人2017;和Li等人2018。
本文所引用的第一作者或发明者的文献的完整引用和年份列于本说明书末尾。
发明内容
在一个方面中,本说明书提供具有式(I)、式(II)或式(III)结构的化合物
其中
R1为(C1-C5烷基)O、(C1-C2烷基)O(CH2)2-3O、(C1-C5烷基)C(=O)O、(C1-C5烷基)NH、(C1-C2烷基)O(CH2)2-3NH或(C1-C5烷基)C(=O)NH;
R2和R3在每次出现时独立地为H、C1-C3烷基、卤素、O(C1-C3烷基)、CN或NO2,其中一个R3可经(CH2)xR4替换,其中下标x为1、2、3或4;
R4为H、卤素、OH、CN、NH2、NH(C1-C5烷基)、N(C1-C5烷基)2、NH(C3-C6环烷基)、NH(C4-C8双环烷基)、NH(C6-C10螺环烷基)、N(C3-C6环烷基)2、NH(CH2)1-3(芳基)、N((CH2)1-3(芳基))2、具有结构的环胺部分、6元芳香族或杂芳香族部分或者5元杂芳香族部分;
其中
烷基、环烷基、双环烷基、螺环烷基、环胺、6元芳香族或杂芳香族部分或者5元杂芳香族部分任选地经一或多个选自以下的取代基取代:OH、卤素、CN、(C1-C3烷基)、O(C1-C3烷基)、C(=O)(Me)、SO2(C1-C3烷基)、C(=O)(Et)、NH2、NH(Me)、N(Me)2、NH(Et)、N(Et)2和N(C1-C3烷基)2;且
环烷基、双环烷基、螺环烷基或环胺部分可具有经O、S、NH、N(C1-C3烷基)或N(Boc)替换的CH2基团;
R5在每次出现时独立地为O、S或NR6;
R6为H或C1-C3烷基;
X1在每次出现时独立地为CR2或N;
X2在每次出现时独立地为CR3或N;且
X3为O、S、NH、N(C1-C3烷基)、C=O或N(C=O)(C1-C3烷基)。
式(I)化合物具有作为TLR7激动剂的活性,且其中一些可经缀合以靶向递送至预期作用的靶组织或器官。
附图说明
图1示出用于制备本发明化合物的代表性方案。
图2和图3示出用于制备激动剂-接头化合物的方案。
图4为示出本发明化合物的TLR7激动作用活性的代表性图。
具体实施方式
定义
“抗体”意指完整抗体及其任何抗原结合片段(即“抗原结合部分”)或单链变体。完整抗体为包含由二硫键相互连接的至少两条重(H)链和两条轻(L)链的蛋白。各重链包含重链可变区(VH)及包含三个域CH1、CH2和CH3的重链恒定区。各轻链包含轻链可变区(VL或Vk)及包含单一域CL的轻链恒定区。VH和VL区可进一步再分成高变区,称为互补决定区(CDR),穿插有较保守框架区(FR)。各VH和VL包含三个CDR和四个FR,其自氨基至羧基端以如下次序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。可变区含有与抗原相互作用的结合域。恒定区可介导抗体与宿主组织或因子的结合,包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分(Clq)。抗体在抗体以5×10-8M或更小、更优选1×10-8M或更小、更优选6×10-9M或更小、更优选3×10-9M或更小、甚至更优选2×10-9M或更小的KD结合于抗原X时称为“特异性结合”于抗原X。抗体可为嵌合抗体、人源化抗体或优选人类抗体。重链恒定区可经工程化改造以影响糖基化类型或程度,延长抗体半衰期,增强或减少与效应细胞或补体系统的相互作用,或调节一些其他性质。工程化改造可通过替换、添加或删除一或多个氨基酸或通过用来自另一免疫球蛋白类型的域替换域或前述方法的组合来完成。
抗体的“抗原结合片段”和“抗原结合部分”(或简单地“抗体部分”或“抗体片段”)意指抗体的保留特异性结合于抗原的能力的一或多个片段。已证实抗体的抗原结合功能可通过全长抗体的片段执行,此类片段诸如(i)Fab片段,其为由VL、VH、CL和CH1域构成的单价片段;(ii)F(ab')2片段,其为包含由铰链区处的二硫桥连接的两个Fab片段的二价片段;(iii)Fab'片段,其基本上为具有铰链区部分的Fab(参见例如Abbas等人,Cellular andMolecular Immunology,第6版,Saunders Elsevier 2007);(iv)Fd片段,其由VH和CH1域组成;(v)Fv片段,其由抗体的单臂的VL和VH域组成;(vi)dAb片段(Ward等人,(1989)Nature341:544-546),其由VH域组成;(vii)经分离的互补决定区(CDR);和(viii)纳米抗体,其为含有单一可变域和两个恒定域的重链可变区。优选的抗原结合片段为Fab、F(ab')2、Fab'、Fv和Fd片段。此外,尽管Fv片段的两个域VL和VH由单独的基因编码,但该域可使用重组方法通过合成接头接合,该合成接头使得该域能够形成为其中VL区与VH区配对形成单价分子的单一蛋白链(称为单链Fv或scFv);参见例如Bird等人(1988)Science 242:423-426;和Huston等人(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。此类单链抗体也涵盖于术语抗体的“抗原结合部分”内。
除非另外规定,否则根据Kabat系统(Kabat等人,“Sequences of proteins ofimmunological interest”,第5版,公开案第91-3242号,美国卫生与公众服务部(U.S.Dept.Health&Human Services),NIH,Bethesda,Md.,1991,以下简称“Kabat”)提及抗体重链或轻链可变区(VH或VL)中氨基酸位置的编号(例如提及SEQ ID NO:清单中的直链编号),且根据如Kabat中所列的EU索引提及抗体重链或轻链恒定区(CH1、CH2、CH3或CL)中氨基酸位置的编号。参见Lazar等人的US 2008/0248028A1,该文献的例如此类使用的公开内容以引用的方式并入本文中。此外,免疫遗传学信息系统(ImMunoGeneTics InformationSystem;IMGT)在其网站提供了名称为“IMGT Scientific Chart:Correspondence betweenC Numberings”的表,其展示其用于重链恒定区的编号系统、EU编号和Kabat编号之间的对应关系。
“经分离抗体”意指基本上不含具有不同抗原特异性的其他抗体的抗体(例如特异性结合抗原X的经分离抗体基本上不含特异性结合除抗原X以外的抗原的抗体)。然而,特异性结合抗原X的经分离抗体可与诸如来自其他物种的抗原X分子的其他抗原具有交叉反应性。在某些实施方案中,经分离抗体特异性结合于人类抗原X且不与其他(非人类)抗原X抗原交叉反应。此外,经分离抗体可基本上不含其他细胞物质和/或化学物质。
“单克隆抗体”或“单克隆抗体组合物”意指具有单一分子组成的抗体分子的制剂,其对特定抗原表位展现单一结合特异性和亲和力。
“人类抗体”意指具有如下可变区的抗体,其中框架区与CDR区(和恒定区(若存在))均衍生自人类生殖系免疫球蛋白序列。人类抗体可包括后续修饰,包括天然或合成修饰。人类抗体可包括并非由人类生殖系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机或定点突变诱发或通过体内体细胞突变引入的突变)。然而,“人类抗体”不包括源自另一哺乳动物物种(诸如小鼠)的生殖系的CDR序列已经移植至人类框架序列上的抗体。
“人类单克隆抗体”意指呈现单一结合特异性的抗体,其具有如下可变区,其中框架区与CDR区均衍生自人类生殖系免疫球蛋白序列。在一个实施方案中,人类单克隆抗体由融合瘤产生,该融合瘤包括与永生化细胞融合的获自转基因非人类动物(例如转基因小鼠)的B细胞,该转基因非人类动物具有包含人类重链转基因和轻链转基因的基因组。
“脂族基”意指直链或支链、饱和或不饱和的非芳香族烃部分,其具有指定数目个碳原子(例如,如在“C3脂族基”、“C1-5脂族基”、“C1-C5脂族基”或“C1至C5脂族基”中,后面三个词组为具有1至5个碳原子的脂族部分的同义词),或在未明确指定碳原子数目时具有1至4个碳原子(在不饱和脂族部分的实例中具有2至4个碳原子)。类似理解适用于其他类型中的碳数目,如在C2-4烯烃、C4-C7环脂族基等中。以类似方式,诸如“(CH2)1-3”的术语应理解为下标为1、2或3的简写,因而此类术语表示CH2、CH2CH2和CH2CH2CH2。
“烷基”意指饱和脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C1-C4烷基部分包括(但不限于)甲基、乙基、丙基、异丙基、异丁基、叔丁基、1-丁基、2-丁基等。“亚烷基”意指烷基的二价对应物,诸如CH2CH2、CH2CH2CH2和CH2CH2CH2CH2。
“烯基”意指具有至少一个碳-碳双键的脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C2-C4烯基部分包括(但不限于)乙烯基(ethenyl/vinyl)、2-丙烯基(烯丙基或丙-2-烯基)、顺-1-丙烯基、反-1-丙烯基、E-(或Z-)2-丁烯基、3-丁烯基、1,3-丁二烯基(丁-1,3-二烯基)等。
“炔基”意指具有至少一个碳-碳三键的脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C2-C4炔基包括乙炔基(ethynyl/acetylenyl)、炔丙基(丙-2-炔基)、1-丙炔基、丁-2-炔基等。
“环脂族基”意指具有1至3个环的饱和或不饱和、非芳香族烃部分,各环具有3至8个(优选3至6个)碳原子。“环烷基”意指其中各环饱和的环脂族部分。“环烯基”意指其中至少一个环具有至少一个碳-碳双键的环脂族部分。“环炔基”意指其中至少一个环具有至少一个碳-碳三键的环脂族部分。以说明的方式,环脂族部分包括(但不限于)环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基和金刚烷基。优选的环脂族部分为环烷基部分,尤其环丙基、环丁基、环戊基和环己基。“亚环烷基”意指环烷基的二价对应物。
“杂环脂族基”意指如下环脂族部分,其中在其至少一个环中,至多三个(优选1至2个)碳经独立地选自N、O或S的杂原子替换,其中N和S可任选地经氧化且N可任选地经季铵化。优选的环脂族部分由大小为5元至6元的一个环组成。类似地,“杂环烷基”、“杂环烯基”和“杂环炔基”分别意指环烷基、环烯基或环炔基部分,其中其至少一个环经如此修饰。例示性杂环脂族部分包括氮杂环丙烷基、氮杂环丁烷基、1,3-二氧杂环己烷基、氧杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、四氢吡喃基、四氢噻喃基、四氢噻喃基砜、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜、1,3-二氧戊环基、四氢-1,1-二氧代噻吩基、1,4-二氧杂环己烷基、硫杂环丁烷基等。“亚杂环烷基”意指杂环烷基的二价对应物。
“烷氧基”、“芳基氧基”、“烷基硫基”和“芳基硫基”分别意指-O(烷基)、-O(芳基)、-S(烷基)和-S(芳基)。实例分别为甲氧基、苯氧基、甲基硫基和苯基硫基。
除非指示较窄含义,否则“卤素”或“卤代”意指氟、氯、溴或碘。
“芳基”意指具有单环、双环或三环环系统(优选单环)的烃部分,其中各环具有3至7个碳原子且至少一个环为芳香族。环系统中的环可彼此稠合(如在萘基中)或彼此键合(如在联苯中)且可与非芳香族环稠合或键合(如在茚满基或环己基苯基中)。以进一步说明的方式,芳基部分包括(但不限于)苯基、萘基、四氢萘基、茚满基、联苯、菲基、蒽基和苊基。“亚芳基”意指芳基的二价对应物,例如1,2-亚苯基、1,3-亚苯基或1,4-亚苯基。
“杂芳基”意指具有单环、双环或三环环系统(优选5元至7元单环)的部分,其中各环具有3至7个碳原子,且至少一个环为含有1至4个独立地选自N、O或S的杂原子的芳环,其中N和S可任选地经氧化且N可任选地经季铵化。此类至少一个含杂原子芳环可与其他类型的环稠合(如在苯并呋喃基或四氢异喹啉基中)或与其他类型的环直接键合(如在苯基吡啶基或2-环戊基吡啶基中)。以进一步说明的方式,杂芳基部分包括吡咯基、呋喃基、噻吩基(thiophenyl或thienyl)、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、四唑基、吡啶基、N-氧代吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉基、喹唑啉基(quinazolinyl)、噌啉基、喹喔啉基(quinozalinyl)、二氮杂萘基、苯并呋喃基、吲哚基、苯并噻吩基、噁二唑基、噻二唑基、苯并噻唑基、苯并咪唑基、苯并三唑基、二苯并呋喃基、咔唑基、二苯并噻吩基、吖啶基等。“亚杂芳基”意指杂芳基的二价对应物。
若据指示部分可经取代,诸如如在“未经取代或经取代的C1-C5烷基”或“任选地经取代的杂芳基”中通过使用“未经取代或经取代”或“任选地经取代”措辞,则此类部分可具有一或多个独立选择的取代基,优选数目为一至五个,更优选数目为一个或两个。取代基和取代模式可由本领域普通技术人员考虑取代基所连接的部分而选择,以提供化学上稳定且可通过本领域中已知的技术以及本文所阐述的方法合成的化合物。若一个部分鉴别为“未经取代或经取代”或“任选地经取代”,则在一优选实施方案中,此类部分未经取代。
“芳基烷基”、“(杂环脂族基)烷基”、“芳基烯基”、“芳基炔基”、“联芳基烷基”等意指烷基、烯基或炔基部分,任选地可经芳基、杂环脂族基、联芳基等部分取代,任选地可在烷基、烯基或炔基部分上具有开放(不饱和)价态,例如如在苯甲基、苯乙基、N-咪唑基乙基、N-吗啉基乙基等中。相反地,“烷基芳基”、“烯基环烷基”等意指芳基、环烷基等部分,任选地可经烷基、烯基等部分取代,任选地可例如如在甲基苯基(甲苯基)或烯丙基环己基中。“羟基烷基”、“卤代烷基”、“烷基芳基”、“氰基芳基”等意指烷基、芳基等部分,任选地可经一或多个所鉴别取代基(视情况可为羟基、卤素等)取代。
举例而言,可容许的取代基包括(但不限于)烷基(尤其甲基或乙基)、烯基(尤其烯丙基)、炔基、芳基、杂芳基、环脂族基、杂环脂族基、卤素(尤其氟)、卤代烷基(尤其三氟甲基)、羟基、羟基烷基(尤其羟基乙基)、氰基、硝基、烷氧基、-O(羟基烷基)、-O(卤代烷基)(尤其-OCF3)、-O(环烷基)、-O(杂环烷基)、-O(芳基)、烷基硫基、芳基硫基、=O、=NH、=N(烷基)、=NOH、=NO(烷基)、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟基烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(环烷基)、-S(=O)烷基、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)、-SO2N(烷基)2等。
若经取代的部分为脂族部分,则优选的取代基为芳基、杂芳基、环脂族基、杂环脂族基、卤素、羟基、氰基、硝基、烷氧基、-O(羟基烷基)、-O(卤代烷基)、-O(环烷基)、-O(杂环烷基)、-O(芳基)、烷基硫基、芳基硫基、=O、=NH、=N(烷基)、=NOH、=NO(烷基)、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟基烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(=O)烷基、-S(环烷基)、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)和-SO2N(烷基)2。更优选的取代基为卤素、羟基、氰基、硝基、烷氧基、-O(芳基)、=O、=NOH、=NO(烷基)、-OC(=O)(烷基)、-OC(=O)O(烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2和-NHC(=NH)NH2。尤其优选的为苯基、氰基、卤素、羟基、硝基、C1-C4烷氧基、O(C2-C4亚烷基)OH和O(C2-C4亚烷基)卤素。
若经取代的部分为环脂族、杂环脂族、芳基或杂芳基部分,则优选的取代基为烷基、烯基、炔基、卤素、卤代烷基、羟基、羟基烷基、氰基、硝基、烷氧基、-O(羟基烷基)、-O(卤代烷基)、-O(芳基)、-O(环烷基)、-O(杂环烷基)、烷基硫基、芳基硫基、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟基烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(环烷基)、-S(=O)烷基、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)和-SO2N(烷基)2。更优选的取代基为烷基、烯基、卤素、卤代烷基、羟基、羟基烷基、氰基、硝基、烷氧基、-O(羟基烷基)、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2和-NHC(=NH)NH2。尤其优选的为C1-C4烷基、氰基、硝基、卤素和C1-C4烷氧基。
若陈述一范围,如同“C1-C5烷基”或“5至10%”,则此类范围包括范围的端点,如同第一实例中的C1和C5及第二实例中的5%和10%。
除非特别指示特定立体异构体(例如通过结构式中相关立构中心的加粗或短划键,通过将结构式中的双键描述为具有E或Z构型或通过使用指明立体化学的命名法),否则所有立体异构体均以纯化合物以及其混合物的形式包括在本发明的范围内。除非另外指明,否则个别对映异构体、非对映异构体、几何异构体及其组合及混合物均由本发明涵盖。
本领域技术人员将了解,化合物可具有互变异构形式(例如酮和烯醇形式)、共振形式和两性离子形式,其等效于本文所用的结构式中所描绘的形式,且该结构式涵盖此类互变异构、共振或两性离子形式。
“药学上可接受的酯”意指体内(例如在人体中)水解产生母体化合物或其盐或自身活性类似于母体化合物的酯。适合的酯包括C1-C5烷基酯、C2-C5烯基酯或C2-C5炔基酯,尤其甲酯、乙酯或正丙酯。
“药学上可接受的盐”意指适用于药物制剂的化合物的盐。若化合物具有一或多个碱性基团,则盐可为酸加成盐,诸如硫酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、马来酸盐、柠檬酸盐、磷酸盐、乙酸盐、双羟萘酸盐(恩波酸盐(embonate))、氢碘酸盐、硝酸盐、盐酸盐、乳酸盐、甲基硫酸盐、富马酸盐、苯甲酸盐、琥珀酸盐、甲磺酸盐、乳糖酸盐、辛二酸盐、甲苯磺酸盐等。若化合物具有一或多个酸性基团,则盐可为如下盐,诸如钙盐、钾盐、镁盐、葡甲胺盐、铵盐、锌盐、哌嗪盐、氨丁三醇盐、锂盐、胆碱盐、二乙胺盐、4-苯基环己胺盐、苄星青霉素(benzathine)盐、钠盐、四甲铵盐等。多晶型结晶形式和溶剂合物也涵盖在本发明的范围内。
一般而言,出于一致性和便利性,在本文中以烯醇形式呈现互变异构结构。
本领域技术人员将了解,该互变异构结构还可以等效酮形式呈现,且两种互变异构体等效。
TLR7激动剂
式(I)中的R1优选为n-BuO、n-BuNH、EtO、MeO或MeOCH2CH2O;更优选为n-BuO或MeOCH2CH2O;且最优选为n-BuO。
在式(I)中,优选地,各R2为H,一个R3经(CH2)xR4替换,且其他R3各自为H。
在一个实施方案中,式(I)化合物由式(Ia)表示,其中R1优选为n-BuO,且下标x优选为1。
在式(I)和式(Ia)中,R4优选为OH、NH(CHMe2)、NHCH2C6H5、NHMe、NHCH2CH2OH、
式(I)化合物的实例包括:
表A呈现本文中所公开的化合物的生物活性数据。一组数据涉及使用HEK-BlueTMTLR7报导测定的TLR7激动作用活性,如下文中所描述。另一组数据涉及白介素6(IL-6)的诱导,白介素6是在TLR7途径中起重要作用的细胞介素。出于比较,也呈现雷西莫特、威沙立德、嘎德莫特和化合物B(CAS登记号226906-84-9)的活性。
缀合物
综述
本文中所公开的TLR7激动剂可通过局部给药或通过以与靶向部分的缀合物形式靶向递送而递送至预期作用位点。优选地,靶向部分为抗体或其抗原结合部分,且其抗原位于预期作用位置,例如若预期作用位点位于肿瘤(癌症)则其抗原为肿瘤相关抗原。优选地,相比于正常细胞,癌细胞唯一表现或过度表现肿瘤相关抗原。肿瘤相关抗原可位于癌细胞表面上或由癌细胞分泌至其环境中。
在一个方面中,提供一种包含本发明化合物和配体的缀合物,其由式(IV)表示
[D(XD)a(C)c(XZ)b]mZ (IV)
其中Z为靶向部分,D为本发明的激动剂,且-(XD)aC(XZ)b-由于它们连接Z与D而统称为“连接部分”或“接头”。在接头内,C为经设计以在D的预期生物学作用位点处或附近裂解的可裂解基团;XD和XZ分别为间隔开D与C及C与Z之间隔部分(或“间隔基”);下标a、b和c独立地为0或1(即,XD、XZ和C任选地存在)。下标m为1、2、3、4、5、6、7、8、9或10(优选1、2、3或4)。D、XD、C、XZ和Z更充分描述于下文中。
通过结合于安置有其抗原或受体的靶组织或细胞,Z将缀合物引导至此处。基团C在标靶组织或细胞处的裂解释放D,从而局部地发挥其效应。以此方式,达成D在预期作用位点的精确递送,从而降低所需剂量。另外,D在处于其缀合状态时通常没有生物活性(或活性明显更低),从而减少脱靶效应。
如由下标m所反映,取决于可供用于缀合的位点Z的数目和所用实验条件,各Z可与多于一个D缀合。本领域技术人员将了解,虽然各个别Z与整数数目个D至和,但是缀合物的制备可分析D与Z的非整数比率,其反映统计平均值。此比率称为取代比率(“SR”)或药物-抗体比率(“DAR”)。
靶向部分Z
优选地,靶向部分Z为抗体。为方便和简洁起见且以非限制方式,本说明书中关于Z及其缀合物的详细论述以其为抗体的情形书写,但本领域技术人员将理解,其他类型的Z也可在细节上作必要修改后缀合。举例而言,带有作为靶向部分的叶酸的缀合物可靶向表面上具有叶酸受体的靶细胞(Leamon等人,Cancer Res.2008,68(23),9839)。出于相同原因,本说明书中的详细论述主要关于1:1比率的Z与D(m=1)书写。
可用于本发明缀合物中的抗体包括识别以下抗原的抗体:间皮素、前列腺特异性膜抗原(PSMA)、CD19、CD22、CD30、CD70、B7H3、B7H4(也称为O8E)、蛋白酪氨酸激酶7(PTK7)、磷脂酰肌醇蛋白聚糖-3、RG1、岩藻糖基-GM1、CTLA-4和CD44。抗体可为动物(例如鼠类)抗体、嵌合抗体、人源化抗体或优选人类抗体。抗体优选为单克隆抗体,尤其单克隆人类抗体。针对前述抗原中的一些的人类单克隆抗体的制备公开于以下文献中:Korman等人,US 8,609,816B2(2013;B7H4,也称为08E;具体为抗体2A7、1G11和2F9);Rao-Naik等人,8,097,703B2(2012;CD19;具体为抗体5G7、13F1、46E8、21D4、21D4a、47G4、27F3和3C10);King等人,US 8,481,683B2(2013;CD22;具体为抗体12C5、19A3、16F7和23C6);Keler等人,US 7,387,776B2(2008;CD30;具体为抗体5F11、2H9和17G1);Terrett等人,US 8,124,738B2(2012;CD70;具体为抗体2H5、10B4、8B5、18E7和69A7);Korman等人,US 6,984,720B1(2006;CTLA-4;具体为抗体10D1、4B6和1E2);Korman等人,US 8,008,449B2(2011;PD-1;具体为抗体17D8、2D3、4H1、5C4、4A11、7D3和5F4);Huang等人,US 2009/0297438A1(2009;PSMA;具体为抗体1C3、2A10、2F5、2C6);Cardarelli等人,US 7,875,278B2(2011;PSMA;具体为抗体4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5和1C3);Terrett等人,US 8,222,375B2(2012;PTK7;具体为抗体3G8、4D5、12C6、12C6a和7C8);Harkins等人,US 7,335,748B2(2008;RG1;具体为抗体A、B、C和D);Terrett等人,US 8,268,970B2(2012;间皮素;具体为抗体3C10、6A4和7B1);Xu等人,US 2010/0092484A1(2010;CD44;具体为抗体14G9.B8.B4、2D1.A3.D12和1A9.A6.B9);Deshpande等人,US 8,258,266B2(2012;IP10;具体为抗体1D4、1E1、2G1、3C4、6A5、6A8、7C10、8F6、10A12、10A12S和13C4);Kuhne等人,US 8,450,464B2(2013;CXCR4;具体为抗体F7、F9、D1和E2);和Korman等人,US 7,943,743B2(2011;PD-L1;具体为抗体3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7和13G4);这些文献的公开内容以引用的方式并入本文中。优选地,抗体为抗间皮素抗体。
除为抗体外,Z还可为抗体片段(诸如Fab、Fab'、F(ab')2、Fd或Fv)或抗体模拟物,诸如亲和抗体(affibody)、单域抗体(dAb)、纳米抗体、单抗体、DARPin、抗运载蛋白(anticalin)、万能抗体(versabody)、双运载蛋白(duocalin)、脂质运载蛋白(lipocalin)或高亲和性多聚体(avimer)。
Z上若干不同反应性基团中的任一个可为缀合位点,包括赖氨酸残基中的ε-氨基、侧链碳水化合物部分、天冬氨酸或谷氨酸侧链上的羧酸基、半胱氨酸-半胱氨酸二硫基和半胱氨酸硫醇基。适用于缀合的抗体反应性基团的综述参见例如Garnett,Adv.DrugDelivery Rev.2001,53,171-216及Dubowchik和Walker,Pharmacology&Therapeutics1999,83,67-123,其公开内容以引用的方式并入本文中。
大部分抗体具有多个赖氨酸残基,其可经由其ε-氨基通过酰胺、脲、硫脲或氨基甲酸酯键而缀合。
可通过若干方法使用半胱氨酸侧链中的硫醇(-SH)基来形成缀合物。该硫醇基可用于在其与接头上的硫醇基之间形成二硫键。另一方法经由与接头上的马来酰亚胺基的迈克尔加成反应(Michael addition)。
通常,尽管抗体具有半胱氨酸残基,但其没有游离的硫醇基,因为其所有半胱氨酸都形成了链内或链间二硫键。为了产生游离的硫醇基,可减少天然二硫基。参见例如Packard等人,Biochemistry 1986,25,3548;King等人,Cancer Res.1994,54,6176;和Doronina等人,Nature Biotechnol.2003,21,778。可替代地,可通过使抗体突变、用半胱氨酸取代另一氨基酸或将半胱氨酸插入多肽链中而引入具有游离-SH基团的半胱氨酸。参见例如Eigenbrot等人,US 7,521,541B2(2009);Chilkoti等人,Bioconjugate Chem.1994,5,504;Urnovitz等人,US 4,698,420(1987);Stimmel等人,J.Biol.Chem.2000,275,30445;Bam等人,US 7,311,902B2(2007);Kuan等人,J.Biol.Chem.1994,269,7610;Poon等人,J.Biol.Chem.1995,270,8571;Junutula等人,Nature Biotechnology 2008,26,925;和Rajpal等人2015年12月21日提交的美国临时申请第62/270245号。在另一方法中,将半胱氨酸添加至重链或轻链的C端。参见例如Liu等人,US 8,865,875B2(2014);Cumber等人,J.Immunol.1992,149,120;King等人,Cancer Res.1994,54,6176;Li等人,BioconjugateChem.2002,13,985;Yang等人,Protein Engineering 2003,16,761;和Olafson等人,Protein Engineering Design&Selection 2004,17,21。本段落中引用的文献的公开内容以引用的方式并入本文中。
接头及其组分
如上文所提及,接头包含多达三个要素:可裂解基团C和任选地存在的间隔基XZ和XD。
基团C在生理条件下可裂解。优选地,基团C在缀合物处于血液循环中时相对稳定,但在缀合物到达其预期作用位点后容易裂解。
优选的基团C为肽,其由靶细胞内的蛋白酶选择性裂解,而不是由血清中的蛋白酶裂解。通常,肽包含1至20个氨基酸,优选1至6个氨基酸,更优选2至3个氨基酸。氨基酸可为天然和/或非天然α-氨基酸。天然氨基酸为由遗传密码编码的氨基酸以及自其衍生的氨基酸,例如羟基脯氨酸、γ-羧基谷氨酸、瓜氨酸和O-磷酸丝氨酸。在本说明书中,术语“氨基酸”还包括氨基酸类似物和模拟物。类似物为如下化合物,其具有天然氨基酸的相同通用H2N(R)CHCO2H结构,但R基团不为天然氨基酸中存在的基团。类似物的实例包括高丝氨酸、正亮氨酸、甲硫氨酸-亚砜和甲硫氨酸甲基锍。氨基酸模拟物为如下化合物,其具有不同于α-氨基酸的通用化学结构的结构,但以类似于α-氨基酸的方式起作用。氨基酸可具有遗传编码氨基酸的“L”立体化学以及对映异构“D”立体化学。
优选地,C含有为蛋白酶的裂解识别序列的氨基酸序列。许多裂解识别序列为本领域中已知的。参见例如Matayoshi等人Science 247:954(1990);Dunn等人Meth.Enzymol.241:254(1994);Seidah等人Meth.Enzymol.244:175(1994);Thornberry,Meth.Enzymol.244:615(1994);Weber等人Meth.Enzymol.244:595(1994);Smith等人Meth.Enzymol.244:412(1994);和Bouvier等人Meth.Enzymol.248:614(1995);其公开内容以引用的方式并入本文中。
基团C可经选择以使得其由癌症附近的细胞外基质中所存在的蛋白酶裂解,该蛋白酶例如附近垂死癌细胞所释放的蛋白酶或癌细胞所分泌的肿瘤相关蛋白酶。例示性细胞外肿瘤相关蛋白酶为纤维蛋白溶酶、基质金属蛋白酶(MMP)、Thimet寡肽酶(TOP)和CD10。参见例如Trouet等人,US 7,402,556B2(2008);Dubois等人,US 7,425,541B2(2008);和Bebbington等人,US 6,897,034B2(2005)。通常为存在于细胞内部的溶酶体酶的组织蛋白酶D有时存在于肿瘤环境中,有可能由垂死癌细胞所释放。
对于经设计以通过酶裂解的缀合物而言,C优选包含经选择以通过诸如组织蛋白酶B、C、D、H、L和S(尤其组织蛋白酶B)的蛋白酶裂解的氨基酸序列。例示性组织蛋白酶B可裂解肽包括Val-Ala、Val-Cit、Val-Lys、Lys-Val-Ala、Asp-Val-Ala、Val-Ala、Lys-Val-Cit、Ala-Val-Cit、Val-Gly、Val-Gln和Asp-Val-Cit。(在本文中,除非上下文明确指示,否则氨基酸序列以N至C方向书写,如同H2N-AA2-AA1-CO2H。)参见Dubowchik等人,Biorg.Med.Chem.Lett.1998,8,3341;Dubowchik等人,Bioorg.Med.Chem.Lett.1998,8,3347;和Dubowchik等人,Bioconjugate Chem.2002,13,855;其公开内容以引用的方式并入。
可用于裂解肽基接头的另一酶为豆荚蛋白,一种优选在Ala-Ala-Asn处裂解的溶酶体半胱氨酸蛋白酶。
在一个实施方案中,基团C为包含两个氨基酸序列-AA2-AA1-的肽,其中AA1为赖氨酸、精氨酸或瓜氨酸,且AA2为苯丙氨酸、缬氨酸、丙氨酸、亮氨酸或异亮氨酸。在另一实施方案中,C由具有一至三个氨基酸的序列构成,其选自由以下组成的群:Val-Cit、Ala-Val、Val-Ala-Val、Lys-Lys、Ala-Asn-Val、Val-Leu-Lys、Cit-Cit、Val-Lys、Ala-Ala-Asn、Lys、Cit、Ser和Glu。更优选地,C为前述群中的两个至三个氨基酸肽。
由单个氨基酸构成的可裂解基团C的制备和设计公开于Chen等人,US 8,664,407B2(2014)中,其公开内容以引用的方式并入本文中。
基团C可直接键合于Z或D;即,间隔基XZ或XD任选地可不存在。
在存在时,间隔基XZ提供C与Z之间的空间分隔,以免前者空间干扰后者的抗原结合或后者空间干扰前者的裂解。此外,间隔基XZ可用于赋予缀合物增加的溶解性或降低的凝集性质。间隔基XZ可包含一或多个模块区段,其可组装于任何数目的组合中。间隔基XZ的适合区段的实例为:
若存在,间隔基XD提供C与D之间的空间分隔,以免后者空间上或电子学上干扰前者的裂解。间隔基XD还可用于将其他分子质量和化学官能团引入缀合物中。一般而言,其他质量和官能团将影响缀合物的血清半衰期及其他性质。因此,经由明智选择间隔基,可调节缀合物的血清半衰期。间隔基XD还可类似于上文关于间隔基XZ的描述由模块区段组装。
间隔基XZ和/或XD在存在时优选在Z与C或D与C之间分别提供4至25个原子、更优选4至20个原子的线性分隔。
除共价连接抗体与药物以外,接头可执行其他功能。举例而言,接头可含有聚(乙二醇)(“PEG”)基团。由于缀合步骤通常涉及在水性介质中将药物-接头偶联至抗体,因此PEG基团可增加药物-接头的水溶解度。另外,PEG基团可增加所得ADC的溶解度或降低其凝集。若存在PEG基团,则可将其并入间隔基XZ或XD或两者中。PEG基团中重复单元的数目可为2至20,优选4至10。
间隔基XZ或XD或两者可包含自分解部分。自分解部分为如下部分,其(1)键合至C以及Z或D中的一个,且(2)具有使得自基团C的裂解启动反应序次的结构,从而使自分解部分自身视情况与Z或D脱离。换言之,远离Z或D的位点处的反应(自基团C的裂解)使得XZ-Z或XD-D键也断裂。自分解部分的存在在间隔基XD的情形下为适宜的,因为若在缀合物裂解后间隔基XD或其一部分保持连接于D,则D的生物活性可能受损。在可裂解基团C为多肽的情形下使用自分解部分为尤其适宜的,在该实例中自分解部分通常邻近于该多肽定位,以便防止D在空间上或在电子学上干扰肽裂解。
键合至D的羟基或氨基的例示性自分解部分(i)至(v)如下所示:
自分解部分为虚线a与b(或虚线b与c)之间的结构,其中展示相邻结构特征以提供背景。自分解部分(i)和(v)键合至D-NH2(即经由氨基缀合),而自分解部分(ii)、(iii)和(iv)键合至D-OH(即经由羟基或羧基缀合)。虚线b处的键由于酶(在结构(i)至(v)的实例中为肽酶且在结构(vi)的实例中为β-葡糖醛酸酶)而发生的裂解启动自分解反应序次,其引起虚线a处的键裂解和视情况D-OH或D-NH2的随后释放。以说明的方式,结构(i)和(iv)的自分解机制如下所示:
换言之,自分解基团的一个部分处的第一化学键的裂解启动一连串步骤,其引起自分解基团的另一部分处的第二化学键(将自分解基团连接至药物的化学键)裂解,从而释放药物。
在一些情况下,自分解基团可串联使用,如结构(vii)所示。在此情况下,虚线c处的裂解触发虚线b与c之间的部分通过1,6-消除反应而自我分解,接着虚线a与b之间的部分通过环化-消除反应而自我分解。关于自分解部分的其他公开案参见Carl等人,J.Med.Chem.1981,24,479;Carl等人,WO 81/01145(1981);Dubowchik等人,Pharmacology&Therapeutics 1999,83,67;Firestone等人,US 6,214,345B1(2001);Toki等人,J.Org.Chem.2002,67,1866;Doronina等人,Nature Biotechnology 2003,21,778(勘误表第941页);Boyd等人,US 7,691,962B2;Boyd等人,US 2008/0279868A1;Sufi等人,WO 2008/083312A2;Feng,US 7,375,078B2;Jeffrey等人,US 8,039,273;和Senter等人,US 2003/0096743A1;其公开内容以引用的方式并入。
在另一实施方案中,Z与D通过不可裂解接头连接,即不存在C。D的代谢最终将接头减小成不会干扰D的生物活性的较小附接部分。
缀合技术
本文中所公开的TLR7激动剂的缀合物优选通过以下方式制得:首先制备包含D和接头(XD)a(C)c(XZ)b(其中XD、C、XZ、a、b和c如针对式(II)所定义)的化合物,以形成由式(V)表示的药物-接头化合物:
D-(XD)a(C)c(XZ)b-R31(V)
其中R31为适用于与Z上的互补官能团反应形成缀合物的官能团。适合基团R31的实例包括氨基、叠氮基、硫醇、环辛炔、
其中R32为Cl、Br、F、甲磺酸酯或甲苯磺酸酯,且R33为Cl、Br、I、F、OH、-O-N-琥珀酰亚胺基、-O-(4-硝基苯基)、-O-五氟苯基或-O-四氟苯基。通常可用于制备适合部分D-(XD)aC(XZ)b-R31的化学方法公开于以下中:Ng等人,US 7,087,600B2(2006);Ng等人,US 6,989,452B2(2006);Ng等人,US 7,129,261B2(2006);Ng等人,WO 02/096910A1;Boyd等人,US 7,691,962B2;Chen等人,US 7,517,903B2(2009);Gangwar等人,US 7,714,016B2(2010);Boyd等人,US 2008/0279868A1;Gangwar等人,US 7,847,105B2(2010);Gangwar等人,US 7,968,586B2(2011);Sufi等人,US 8,461,117B2(2013);和Chen等人,US 8,664,407B2(2014);其公开内容以引用的方式并入本文中。
优选地,反应性官能团-R31为-NH2、-OH、-CO2H、-SH、马来酰亚胺基、环辛炔、叠氮基(-N3)、羟基氨基(-ONH2)或N-羟基琥珀酰亚胺基。尤其优选的官能团-R31为:
-OH基团可用抗体上(例如天冬氨酸或谷氨酸侧链上)的羧基酯化。
-CO2H基团可用抗体上的-OH基团酯化或用抗体上(例如赖氨酸侧链上)的氨基酰胺化。
N-羟基琥珀酰亚胺基为功能上活化的羧基且可便利地通过与氨基(例如赖氨酸的氨基)反应酰胺化。
马来酰亚胺基可与抗体上的-SH基团(例如来自半胱氨酸或来自引入硫氢基官能团的抗体的化学修饰)在迈克尔加成反应中缀合。
若抗体不具有用于缀合的半胱氨酸-SH,则赖氨酸残基侧链中的ε-氨基可与2-亚氨基硫杂环戊烷或N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丙酸酯(“SPDP”)反应以引入游离的硫醇(-SH)基,从而实际上产生半胱氨酸替代物。硫醇基可与马来酰亚胺或其他亲核试剂受体基团反应以实现缀合。下方示出2-亚氨基硫杂环戊烷情形下的机制。
通常,达成每个抗体二至三个硫醇的硫醇化水平。代表性操作参见Cong等人,US8,980,824B2(2015),其公开内容以引用的方式并入本文中。
在相反配置中,可以用4-(马来酰亚胺基甲基)-环己甲酸N-琥珀酰亚胺基酯(“SMCC”)或其磺化变体磺基-SMCC(该两者可购自Sigma-Aldrich)修饰抗体Z,以向其中引入马来酰亚胺基。随后,可使用接头上具有-SH基团的药物-接头化合物来实现缀合。
替代缀合方法使用无铜“点击化学法(click chemistry)”,其中将叠氮基添加在应变环辛炔上以形成1,2,3-三唑环。参见例如Agard等人,J.Amer.Chem.Soc.2004,126,15046;Best,Biochemistry 2009,48,6571,其公开内容以引用的方式并入本文中。叠氮基可位于抗体上且环辛炔位于药物-接头部分上或反之亦然。优选的环辛炔基为二苯并环辛炔(DIBO)。具有DIBO基团的各种试剂可获自Invitrogen/Molecular Probes,Eugene,Oregon。以下反应说明DIBO基团连接于抗体(Ab)的情况下的点击化学法缀合:
另一缀合技术涉及将非天然氨基酸引入抗体中,其中非天然氨基酸提供用于与药物部分中的反应性官能团缀合的官能团。举例而言,非天然氨基酸对乙酰基苯丙氨酸可并入抗体或其他多肽中,如Tian等人,WO 2008/030612A2(2008)中所教导。对乙酰基苯丙氨酸中的酮基可经由与接头-药物部分上的羟基氨基形成肟而成为缀合位点。替代地,可将非天然氨基酸对叠氮基苯丙氨酸并入抗体中,得到叠氮基官能团以如上所述经由点击化学法缀合。非天然氨基酸还可使用无细胞方法而并入抗体或其他多肽中,如Goerke等人,US 2010/0093024A1(2010)和Goerke等人,Biotechnol.Bioeng.2009,102(2),400-416中所教示。前述公开内容以引用的方式并入本文中。因此,在一个实施方案中,用于制备缀合物的抗体具有一或多个经非天然氨基酸替换的氨基酸,该非天然氨基酸优选为对乙酰基苯丙氨酸或对叠氮基苯丙氨酸,更优选为对乙酰基苯丙氨酸。
根据Jeger等人,Angew.Chem.Int.Ed.2010,49,9995,另一缀合技术使用谷氨酰胺转氨酶(优选为来自茂源链霉菌(Streptomyces mobaraensis)的细菌性谷氨酰胺转氨酶或BTG)。BTG在谷氨酰胺的侧链甲酰胺(胺受体)与亚烷基氨基(胺供体)(其可为例如赖氨酸的ε-氨基或5-氨基-正戊基)之间形成酰胺键。在典型缀合反应中,如下所示,谷氨酰胺残基位于抗体上,而亚烷基氨基位于接头-药物部分上:
谷氨酰胺残基位于多肽链上对其对BTG介导的转酰胺作用的敏感性具有很大影响。抗体上的谷氨酰胺残基通常均不为BTG底物。然而,若抗体去糖基化,糖基化位点为重链的天冬酰胺297(N297;根据如Kabat等人,“Sequences of proteins of immunologicalinterest”,第5版,公开案第91-3242号,美国健康与人类服务部(U.S.Dept.Health&HumanServices),NIH,Bethesda,Md.,1991;下文简称“Kabat”中所阐述的EU索引编号),则邻近的谷氨酰胺295(Q295)表现为BTG敏感的。抗体可通过用PNGase F(肽-N-糖苷酶F)处理而以酶方式去糖基化。替代地,抗体可通过在恒定区中引入N297A突变而以无糖苷的形式合成,从而去除N297糖基化位点。此外,已证实N297Q取代不仅去除糖基化,且也引入同样为胺受体的第二谷氨酰胺残基(在位置297处)。由此,在一个实施方案中,抗体去糖基化。在另一实施方案中,抗体具有N297Q取代。本领域技术人员将了解,通过合成后修饰或通过引入N297A突变进行的去糖基化使每个抗体产生二个BTG反应性谷氨酰胺残基(每条重链一个,在位置295处),而具有N297Q取代的抗体将具有四个BTG反应性谷氨酰胺残基(每条重链两个,在位置295和297处)。
通过向抗体中引入含有谷氨酰胺的肽或“标签”,抗体也可表现为对BTG介导的缀合敏感,例如Pons等人,US 2013/0230543A1(2013)和Rao-Naik等人,WO 2016/144608A1中所教导。
在补充方法中,可通过改变BTG的氨基酸序列而改变其底物特异性,使得其变得能够与未经修饰抗体中的谷氨酰胺295反应,如Rao-Naik等人,WO 2017/059158A1(2017)中所教导。
虽然最常用的细菌性谷氨酰胺转氨酶为来自茂源链霉菌的细菌性谷氨酰胺转氨酶,但也可考虑来自底物特异性略微不同的其他细菌的谷氨酰胺转氨酶,诸如来自拉达卡链轮丝菌(Streptoverticillium ladakanum)的谷氨酰胺转氨酶(Hu等人,US 2009/0318349A1(2009)、US 2010/0099610A1(2010)和US 2010/0087371A1(2010))。
具有伯或仲烷基胺的本发明TLR7激动剂尤其适合于以缀合物形式使用,因为仲胺提供用于连接接头的官能团。此类TLR7激动剂-接头化合物的实例为化合物8,其含有酶促可裂解接头。图2示出可据其制备化合物8的方案。
含有非酶促可裂解接头的TLR7激动剂-接头化合物的实例为化合物10。图3示出用于合成化合物10的方案。
化合物8和8均含有伯烷基氨基,使得其能够与谷氨酰胺转氨酶缀合。下文实例中描述适合的缀合操作。
还可使用分选酶A(Sortase A)来实现缀合,如Levary等人,PLoS One 2011,6(4),e18342;Proft,Biotechnol.Lett.2010,32,1-10;Ploegh等人,WO 2010/087994A2(2010);和Mao等人,WO 2005/051976A2(2005)中所教导。分选酶A识别基序(通常LPXTG,其中X为任何天然氨基酸)可位于配体Z上,且亲核性受体基序(通常GGG)可为式(III)中的基团R31,或反之亦然。
TLR7激动剂缀合物
应用前述技术,可制备TLR7激动剂缀合物,诸如下方所示的缀合物:
其中m为1、2、3或4,且Ab为抗体。
聚乙二醇化
将聚(乙二醇)(PEG)链连接至药物(“聚乙二醇化”)可改善药物的药物动力学特性。药物的循环半衰期增加,有时增加超过一个数量级,同时降低了达成所要治疗效果所需要的剂量。聚乙二醇化还可减少药物的代谢降解且降低其免疫原性。综述参见Kolate等人,J.Controlled Release 2014,192,167。
聚乙二醇化最初应用于生物药物。截至2016年,已批准超过十种聚乙二醇化生物制剂。Turecek等人,J.Pharmaceutical Sci.2016,105,460。最近,受该理论于生物制剂中成功应用的刺激,人们注意力已转向其于小分子药物中的应用。除前述益处外,聚乙二醇化小分子药物可具有增加的溶解度且引起较少毒性作用。Li等人Prog.Polymer Sci.2013,38,421。
本文所公开的化合物可经聚乙二醇化,即具有与其共价键合的聚(乙二醇)部分。在化合物具有脂族羟基或脂族伯或仲胺时,诸如化合物Ia-01或Ia-04(箭头)的情形,该化合物可利用常规技术(诸如二环己基碳二亚胺、HATU、N-羟基琥珀酰亚胺酯等)通过含有羧基的PEG分子经由酯基、酰氨基、碳酸酯基或氨基甲酸酯基而聚乙二醇化。用于对药物分子进行聚乙二醇化的各种其他方法公开于Alconcel等人,Polymer Chem.2011,2,1442中,其公开内容以引用的方式并入本文中。
视需要,本文中所公开的TLR7激动剂可经由包含自分解部分的酶促可裂解接头聚乙二醇化,从而允许未经聚乙二醇化的激动剂以设计方式释放。此外,若含有PEG的分子具有用于连接至蛋白的适合官能团(诸如胺),则聚乙二醇化可与该蛋白(诸如抗体)的缀合组合。蛋白可提供额外治疗功能,或在抗体的情况下可提供靶向功能。在下方反应序次中示出这些理论,其中TLR7-NH-R通常表示TLR7激动剂:
在上述反应序次中,缬氨酸-瓜氨酸(Val-Cit)二肽可通过组织蛋白酶B裂解,其中对氨基苯甲基氧基羰基(PABC)充当自分解间隔基。用于缀合的官能团为胺基,其暂时受Fmoc基团保护。缀合由谷氨酰胺转氨酶实现,其中谷氨酰胺(Gln)侧链充当酰基受体。取决于聚乙二醇化的目的,表示PEG重复单元的数目的下标x可广泛变化,如下文所论述。出于一些目的,x可相对较小,诸如2、4、8、12或24。出于其他目的,x较大,例如介于约45至约910之间。
本领域技术人员将理解,该序次为说明性的,且可使用如本领域中所熟知的其他要素(肽、自分解基团、缀合方法、PEG长度等)。本领域技术人员还将理解,虽然上述序次组合聚乙二醇化与缀合,但聚乙二醇化不需要缀合。且反之亦然。
在化合物没有脂族羟基或脂族伯或仲胺时,如在化合物Ia-09的情形中,仍然可在芳胺(箭头)处聚乙二醇化。在该位置处进行聚乙二醇化的方法由Zarraga,US 2017/0166384A1(2007)公开,其公开内容以引入的方式并入。
在一些实施方案中,可能需要单个分子中连接有多个聚乙二醇化激动剂。举例而言,可在季戊四醇(C(CH2OH)4)上构筑四个聚乙二醇化臂,且TLR7激动剂可连接至各聚乙二醇化臂。参见Gao等人,US 2013/0028857A1(2013),其公开内容以引用的方式并入。
为了调节药物动力学,通常优选的是PEG部分的分子量介于约2kDa(对应于约45个-(CH2CH2O)-重复单元)至约40kDa(对应于约910个-(CH2CH2O)-重复单元)之间,更优选介于约5kDa至约20kDa之间。即,上式中下标x的范围为约45至约910。应理解,PEG组合物并非100%均质的,而是实际上呈现分子量分布。因此,例如对“20kDa PEG”的提及意指具有20kDa的平均分子量的PEG。
聚乙二醇化还可用于改善激动剂的溶解度。在此类情况下,可使用较短PEG链,例如包含2、4、8、12或24个重复单元。
实施例
可参考以下实施例进一步理解本发明的实践,其以说明方式提供且不意指具有限制性。
实施例1-TLR7激动剂的合成
本实施例和图1涉及本发明化合物的合成。
在0℃用NaBH4(0.562g,14.85mmol)逐份处理10-甲基-10H-吩噻嗪-3,7-二甲醛1(根据Synthesis,1998,1107制备)(2.00g,7.43mmol)于MeOH(30mL)和THF(15mL)中的悬浮液,且随后在持续冷却下搅拌45分钟。LCMS指示反应完成。反应物用水淬灭且用EtOAc(3×100mL)萃取。有机萃取物经Na2SO4干燥,过滤且浓缩,得到二甲醇2(2.03g,94%产率)。LCMSESI:C15H15NO2S的计算值=274.1(M+H+),实验值274.0(M+H+)。
将二甲醇2(2.43g,8.89mmol)溶解于N.N-二甲基甲酰胺(DMF,30mL)中。添加咪唑(2.421g,35.6mmol),接着在0℃逐滴添加叔丁基二甲基甲硅烷基氯(TBS-Cl,0.804g于5mlDMF中,5.33mmol)。在0℃搅拌3小时后,根据LCMS反应完成。反应物用水淬灭且用EtOAc(4×50mL)萃取。有机萃取物经Na2SO4干燥,过滤且浓缩。粗产物经80g硅胶柱纯化,用EtOAc:己烷(0-100%梯度)洗脱,得到化合物3(1.57g,45.6%产率)。LCMS ESI:C21H29NO2SSi的计算值=388.2(M+H+),实验值388.0(M+H+)。
将化合物3(510mg,1.316mmol)溶解于二氯甲烷(DCM,7.5mL)中,随后添加二异丙基乙胺(DIPEA,0.483mL,2.76mmol),接着在0℃添加甲磺酰氯(MsCl,0.133mL,1.710mmol)。在0℃搅拌1小时后,根据LCMS反应完成。添加DCM(10mL)和水(10mL)并混合。移除水,且用水洗涤反应混合物多于一次。有机层经Na2SO4干燥,过滤且浓缩,得到粗制氯甲基化合物4(582mg),最初形成的甲磺酸酯已原位转化成氯甲基化合物。
氯甲基化合物4在碳酸铯存在下与化合物5(CAS登记号866268-31-7)反应,得到化合物6。
用HCl处理化合物6,得到羟基甲醇Ia-01,其随后通过用亚硫酰氯处理而转化成氯甲基化合物Ia-09。
最后,化合物Ia-09与环丁胺反应,得到化合物Ia-06。LCMS ESI:C28H33N7O2S的计算值=532.2(M+H+),实验值532.0(M+H+)。1H NMR(DMSO-d6)7.16-7.07(m,4H),6.86(dd,J=12.5,8.5 2H),6.56(s,2H),4.76(s,2H),4.18(t,J=6.5Hz,2H),3.51(s,2H),3.12(p,J=7.5Hz,1H),2.07-2.02(m,2H),1.70-1.50(m,6H),1.40(h,J=7.5Hz,2H),0.93(t,J=7.5Hz,3H)。对应于吩噻嗪环的N-Me的信号由于水抑制而不存在。
大体上遵循前述操作,使用替代胺制备如下表B中所示的其他式(I)化合物
本领域技术人员将了解,可遵循上述操作但在细节上作必要修改来制备本说明书的其他化合物。举例而言,化合物
(即,式(I)中的各R2和R3为H的实施例)可通过使用一元醛(CAS登记号4997-36-8)作为起始物质制备:
其中R3基团为Me的化合物可通过对化合物Ia-09进行还原性脱卤制备:
实施例2-TLR7激动剂活性测定
本实施例描述一种用于测定本说明书中所公开的化合物的TLR7激动剂活性的方法。
将经工程化改造的具有人类TLR7分泌的胚胎碱性磷酸酶(SEAP)报导转基因的人类胚胎肾蓝色细胞(HEK-BlueTMTLR细胞;Invivogen)悬浮于非选择性培养基(DMEM高葡萄糖(Invitrogen),其补充有10%胎牛血清(Sigma))中。将HEK-BlueTMTLR7细胞添加至384孔组织培养板中的各孔(每孔15,000个细胞),且在37℃、5%CO2培育16至18小时。将化合物(100nl)施配至含有HEK-BlueTMTLR细胞的孔中,且将经处理细胞在37℃、5%CO2进行培育。处理18小时后,将10微升新制的Quanti-BlueTM试剂(Invivogen)添加至各孔,培育30分钟(37℃,5%CO2),且使用Envision读板器(OD=620nm)来测量SEAP含量。计算半数最大有效浓度值(EC50;诱导测定基线与最大值之间一半反应的化合物浓度)。
图4为展示由此获得的化合物Ia-04的数据的代表性图。
实施例3-谷氨酰胺转氨酶介导的缀合
以下操作可用于谷氨酰胺转氨酶介导的激动剂-接头化合物缀合,其中接头具有可充当胺供体的胺基。抗体可为具有谷氨酰胺转氨酶反应性谷氨酰胺的抗体,例如具有N297A或N297Q取代的抗体。缀合通过重组细菌性谷氨酰胺转氨酶进行,其中抗体:酶的摩尔比为5:1。缀合使用标准方案于50mM Tris缓冲液(pH 8.0)中在37℃培育过夜进行。在用50mM Tris(pH 8.0)预平衡的蛋白A柱上纯化所得缀合物。将缀合物用0.1M柠檬酸钠缓冲液(pH 3.5)洗脱。用1M Tris(pH 9.0)中和洗脱的级分。可在20mg/mL山梨糖醇、10mg/mL甘氨酸(pH 5.0)中调配缀合物。
实施例4-白介素6诱导测定
本实施例描述一种用于测定本说明书中所公开的化合物的白介素6诱导的方法。
使用ECHO声学液体操作技术将于DMSO中稀释的化合物转移至MatrixTechnologies透明V底384孔盘的各个孔中(每孔25nL)。使用CyBio FeliX液体操作仪将人类全血样品(25μL)添加至各孔。将培养板在培养板震荡器上震荡3分钟,之后在37℃培育反应混合物20小时。随后向各孔中添加Basel RPMI 1640培养基(补充有L-谷氨酰胺)(每孔25μL),之后通过离心(450×g,5分钟,环境温度)自各样品释放出血浆。随后使用FeliX液体操作仪将处理后的血浆样品(3μL)转移至白色浅孔的384孔ProxiPlate(Perkin Elmer)的各个孔中,且使用如制造商PerkinElmer所描述的AlphaLISA技术来测量其白介素6含量。使用数据分析软件来确定化合物EC50值,其中使用平均DMSO值确定基线,且使用最高所测试浓度的参考化合物值确定100%诱导。可使用诸如Graphpad PrismTM的软件确定EC50。
本领域技术人员将理解,本实施例中的条件和方法为说明性且非限制性的,且其变化形式或其他缀合方法为本领域中已知的且可用于本发明中。
本发明的前述详细描述包括主要或仅涉及本发明的特定部分或方面的段落。应了解,出于明晰和便利的目的,特定特征可不仅在公开该特征的段落中相关,且本文的公开内容包括不同段落中存在的信息的所有适当组合。类似地,尽管本文的各种图和描述涉及本发明的特定实施方案,但应了解,若特定特征公开于特定图或实施方案的情形下,则此类特征通常还可以适当程度与另一特征组合用于另一图或实施方案的情形下或本发明中。
此外,尽管本发明尤其关于某些优选实施方案进行描述,但本发明并不限于此类优选实施方案。确切而言,本发明的范围通过所附权利要求书界定。
参考文献
下文提供以下参考文献的完整引用,之前在本说明书中这些参考文献以简化方式以第一作者(或发明者)和日期形式引用。这些参考文献各自以引用的方式并入本文中以用于所有目的。
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Akinbobuyi et al.,ACS 2015 Joint Southeastern/Southwest RegionalMeeting,Abstract 392,“Synthesis of functionalized purine analogs for antibodyconjugation”[2015a].
Akinbobuyi et al.,Tetrahedron Lett.2015,56,458,“Facile syntheses offunctionalized toll-like receptor 7 agonists”[2015b].
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Claims (9)
1.一种化合物,其具有根据式(I)、式(II)或式(III)的结构
其中
R1为(C1-C5烷基)O、(C1-C2烷基)O(CH2)2-3O、(C1-C5烷基)C(=O)O、(C1-C5烷基)NH、(C1-C2烷基)O(CH2)2-3NH或(C1-C5烷基)C(=O)NH;
R2和R3在每次出现时独立地为H、C1-C3烷基、卤素、O(C1-C3烷基)、CN或NO2,其中一个R3可经(CH2)xR4替换,其中下标x为1、2、3或4;
R4为H、卤素、OH、CN、NH2、NH(C1-C5烷基)、N(C1-C5烷基)2、NH(C3-C6环烷基)、NH(C4-C8双环烷基)、NH(C6-C10螺环烷基)、N(C3-C6环烷基)2、NH(CH2)1-3(芳基)、N((CH2)1-3(芳基))2、具有结构的环胺部分、6元芳香族或杂芳香族部分或者5元杂芳香族部分;
其中
烷基、环烷基、双环烷基、螺环烷基、环胺、6元芳香族或杂芳香族部分或者5元杂芳香族部分任选地经一或多个选自以下的取代基取代:OH、卤素、CN、(C1-C3烷基)、O(C1-C3烷基)、C(=O)(Me)、SO2(C1-C3烷基)、C(=O)(Et)、NH2、NH(Me)、N(Me)2、NH(Et)、N(Et)2和N(C1-C3烷基)2;且
环烷基、双环烷基、螺环烷基或环胺部分可具有经O、S、NH、N(C1-C3烷基)或N(Boc)替换的CH2基团;
R5在每次出现时独立地为O、S或NR6;
R6为H或C1-C3烷基;
X1在每次出现时独立地为CR2或N;
X2在每次出现时独立地为CR3或N;且
X3为O、S、NH、N(C1-C3烷基)、C=O或N(C=O)(C1-C3烷基。
5.根据权利要求4所述的化合物,其中R1为n-BuO且下标x为1。
7.根据权利要求1所述的化合物,其与抗体缀合。
8.根据权利要求1所述的化合物,其与大小介于2kDa至40kDa之间的聚(乙二醇)部分共价键合。
9.一种治疗患有适合于通过活化Toll样受体7治疗的病状的受试者的方法,包括向此类受试者给予治疗有效量的根据权利要求1所述的化合物。
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EP3668868A1 (en) | 2020-06-24 |
TW201920183A (zh) | 2019-06-01 |
US20190055244A1 (en) | 2019-02-21 |
ES2895369T3 (es) | 2022-02-21 |
CN111225918B (zh) | 2024-01-19 |
EP3668868B1 (en) | 2021-09-22 |
KR20200041911A (ko) | 2020-04-22 |
JP7194170B2 (ja) | 2022-12-21 |
WO2019035969A1 (en) | 2019-02-21 |
US10981914B2 (en) | 2021-04-20 |
US10457681B2 (en) | 2019-10-29 |
JP2020531469A (ja) | 2020-11-05 |
AR112687A1 (es) | 2019-11-27 |
US20200017501A1 (en) | 2020-01-16 |
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